Results of a number of studies indicate that the glutamate system, especially the N-methyl-D-aspartate (NMDA) receptor, has a major function in chronic alcoholism, including craving. Homocysteine and other excitatory amino acids, such as glutamate and aspartate, lead to an overstimulation of NMDA receptors. Because alcoholism is associated with elevated plasma homocysteine concentrations, we designed the current study to determine whether elevated plasma homocysteine concentrations have an influence on craving in alcohol withdrawal. Two groups of patients with an established diagnosis of alcohol dependence were compared. Group A comprised 50 consecutively admitted alcohol-dependent individuals who had been abstinent from alcohol between 24 and 72 h before hospitalization. Group B comprised 146 consecutively recruited alcohol-dependent individuals who were admitted, acutely intoxicated, for withdrawal treatment. All patients were assessed with the Obsessive Compulsive Drinking Scale (OCDS) on the day of admission and after 7 days of treatment. The mean (27.1, S.D. 18.4) plasma homocysteine concentration for group B was significantly higher than the mean (12.5, S.D. 5.3) plasma homocysteine concentration for group A (Mann-Whitney U test: P < .001). No significant influence of homocysteine concentration on the extent of craving was found for either group with the use of the Spearman correlation (day 0: group A, r = -.076, P = .601; group B, r = .120, P = .148) and logistic regression analysis. Although homocysteine is a potent modulator of glutamatergic neurotransmission, results of the current study provide no evidence for a pathophysiologic role of homocysteine in withdrawal craving. Therefore, further research about alcohol craving should focus on neurobiologic factors other than homocysteine.